666P - Final results of phase I/II study of NUC-7738 as monotherapy and in combination with pembrolizumab: Anti-tumor immune response in PD-1 inhibitor-resistant patients

Background

NUC-7738 is a phosphoramidate modification of 3’-deoxyadenosine (3’-dA) designed to generate high intracellular levels of the anti-cancer metabolite 3’-dATP. Our translational studies show that NUC-7738 disrupts RNA polyadenylation, leading to alterations in protein and non-coding RNA levels and promoting anti-tumor immunity.

Methods

NUC-7738 monotherapy was explored in Phase 1 dose escalation (n=38) and Phase 2 dose refinement (n=11) in pts with advanced solid tumors. NUC-7738 + pembrolizumab (Phase 2) was then investigated in 12 pts with metastatic cutaneous melanoma (1-3 prior lines, including ≥1 PD-1 inhibitor). Paired biopsies were taken pre- and post-treatment to evaluate changes in the TME with long read RNA sequencing and multiplex immunofluorescence.

Results

NUC-7738 monotherapy demonstrated a favorable safety profile and evidence of anti-tumor activity in solid tumors. The MTD and RP2D were determined to be 1350 mg/m² and 1125 mg/m² respectively. In the NUC-7738 + pembrolizumab cohort of pts with melanoma, resistant to prior PD-1 inhibitors, 2 PRs were observed at 8 weeks (-55%; DOR 8 months) and 24 weeks (-32%; DOR 2 months, remains on treatment). Seven additional pts had SD for >3 months (range; 3-11). The DCR at 8 weeks was 75%. Four pts remain in PFS follow up. Nausea (9 pts), ALT increased (6 pts), and diarrhea (6 pts) were the most frequent TRAEs (mostly Grade 1 or 2). Four pts had Grade 3 TRAEs: abdominal pain & diarrhea; vomiting & fatigue; hypotension & adrenal insufficiency; AST/ALT increased; GGT increased & immune-mediated hepatitis. One pt had a Grade 4 TRAE of AST/ALT increased. Evaluation of paired biopsies revealed that NUC-7738 disrupted RNA polyadenylation, particularly in long non-coding RNA; mRNA pathway analysis showed evidence of increased T cell activation and antigen presentation post-treatment.

Conclusions

NUC-7738 has a favorable safety profile with promising anti-tumor activity as monotherapy and in combination with pembrolizumab. By disrupting RNA polyadenylation, NUC-7738 alters mRNA half-life and expression of immune regulatory proteins, leading to anti-tumor immune response in patients with PD-1 resistance.

Clinical trial identification

NCT03428958.

Editorial acknowledgement

Legal entity responsible for the study

NuCana.

Funding

NuCana.

Disclosure

S. Blagden: Financial Interests, Personal, Other, Honoraria: Amphista, Theolytics, UCB, Rapport Global; Financial Interests, Personal and Institutional, Research Funding: NuCana, Redx Pharma, UCB, Mina Therapeutics, Astex, Nurix, BerGenBio, MSD Oncology; Financial Interests, Personal, Advisory Board: UCB, Oxford Investment Consultants. M. Elshani: Financial Interests, Personal, Full or part-time Employment: NuCana; Financial Interests, Personal, Stocks/Shares: NuCana. S.N. Symeonides: Financial Interests, Institutional, Advisory Board: Ellipses, Medannex, Eisai, MSD, Pfizer, Merck Serono, Duke Street Bio, Exscientia, Grey Wolf Therapeutics, Roche; Financial Interests, Institutional, Invited Speaker: Ipsen, MSD, Roche, Eisai; Financial Interests, Institutional, Other, Independent Data / Safety Monitoring: Valley Health, Exscientia, Grey Wolf Therapeutics; Financial Interests, Institutional, Full or part-time Employment, Medical Advisor in CRUK's Cente for Drug Development: Cancer Research UK (charity); Financial Interests, Institutional, Research Grant: MSD, Verastem; Financial Interests, Institutional, Coordinating PI: MSD, BioNTech, Nouscom; Financial Interests, Institutional, Steering Committee Member: Roche, Nucana, Sapience Therapeutics, BioLineRx, Boston Pharmaceuticals, Sierra Oncology, Incyte, Scancell, Medannex; Non-Financial Interests, Member of Board of Directors, Non-profit organisation connecting stakeholders in cancer drug development: Cancer Drug Development Forum; Other, Conference attendance (no personal gain): Ipsen, EUSA, MSD, BioNTech. A. Skolariki: Financial Interests, Personal and Institutional, Research Grant: NuCana. A. Dickson, F.G. McKissock, E. Oelmann, J. Bloss: Financial Interests, Personal, Full or part-time Employment: NuCana; Financial Interests, Personal, Stocks/Shares: NuCana. N. Cook: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Local PI: Taiho, Roche, AstraZeneca, Avacta, Bayer, Eisai, UCB, Boeringher, Stemline; Financial Interests, Institutional, Coordinating PI: RedX, Orion, Starpharma, Loxo Oncology; Non-Financial Interests, Advisory Role: Roche; Non-Financial Interests, Other, Committee chair: Cancer Research UK. T.R.J. Evans: Financial Interests, Institutional, Advisory Board for GI cancers and melanoma (immune checkpoint inhibitors): Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, Invited speaker - GI cancers, melanoma, immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Boards - GI cancers, melanoma: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Invited speaker GI cancer, melanoma: Roche/Genentech; Financial Interests, Institutional, Advisory Board (Lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board: MSD, AstraZeneca, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Board: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees: Nucana; Financial Interests, Institutional, Advisory Board; Chair of Scientific Advisory Council (HCC & MIV-818): Medivir; Financial Interests, Institutional, Invited Speaker, speaker's fees (and presentation to potential investors): Medivir; Financial Interests, Personal, Other, Support to attend international conferences: Bristol Myers Squibb, Roche / Genentech, MSD, Nucana, Bayer, Celgene, Pierre Fabre; Financial Interests, Institutional, Advisory Board for Upper GI Cancer: Ascelia; Financial Interests, Institutional, Advisory Board for Oesophageal Cancer: Seagen; Financial Interests, Institutional, Coordinating PI, Educational grant (supply of study agents) for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Local PI, reimbursement of study costs for commercial studies: Astellas, Bayer, Basilea, Celgene, GSK, Roche, Medivir, Starpharma, Immunocore, Novartis, Sapience Therapeutics, MiNa Therapeutics, Lilly, Bicycle Therapeutics, Sierra, CytomX, BeiGene, Pfizer, Johnson & Johnson, UCB, Codiak, Avacta, Nurix, T3P, Amgen, Moderna; Financial Interests, Institutional, Coordinating PI, reimbursement of study costs for commercial studies: Adaptimmune, Bristol Myers Squibb, Eisai, MSD, Nucana, iOnctura, Sanofi; Financial Interests, Institutional, Local PI, support for non-commercial investigator-led study: Verastem; Financial Interests, Institutional, Local PI, reimbursement for costs of commercial studies: Boehringer Ingelheim; Financial Interests, Institutional, Local PI, reimbursement of costs of commercial study: Seagen; Financial Interests, Institutional, Funding, reimbursement of study costs for commercial studies; lead investigator for infrastructure investment to NHS Research Scotland: BioNTech; Financial Interests, Institutional, Local PI, reimbursement of study sots for commercial studies: Exelixis; Non-Financial Interests, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Institutional, Product Samples, Supply of investigational and licensed compounds for a non-commercial study for which I'm Chief Investigator: AstraZeneca; Non-Financial Interests, Member, Cancer Society Member: American Society of Clinical Oncology, America Association for Cancer Research, British Association for Cancer Research, Association of Cancer Physicians (UK), European Association for Cancer Research, International Liver Cancer Association; Other, Editor-in-Chief: British Journal of Cancer; Other, Chair of Independent Data Monitoring Committee for a phase 1 trial - honorarium payable to the employing institution: Genmab; Other, Chair and panel member, Scientific Evaluation Committee: early phase trials (Amgen, Merck, AstraZeneca); Chair and panel member, CLIP (early phase trial centres) 5-year review: Institut National du Cancer (France); Other, Panel Member, Pancreas Cancer funding committee, 2023: Fondation ARC; Other, NHS Research Scotland cancer research network national clinical lead: NHS Research Scotland. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Faber, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapetics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo, Incyte; Financial Interests, Institutional, Royalties, Royalties relating to rucaparib licencing: Clovis Oncology; Financial Interests, Personal, Other, Honorarium as member of IDMC: SOTIO, Alligator Biosciences, AstraZeneca; Financial Interests, Personal, Other, Honoraria as member of IDMC: GSK. D.J. Harrison: Financial Interests, Personal, Full or part-time Employment: NuCana; Financial Interests, Institutional, Research Funding: NuCana; Financial Interests, Personal, Stocks/Shares: NuCana. All other authors have declared no conflicts of interest.